A novel dual kinase function of the RET proto-oncogene negatively regulates activating transcription factor 4-mediated apoptosis.

The Journal of Biological Chemistry
Rozita Bagheri-YarmandRobert F Gagel

Abstract

The RET proto-oncogene, a tyrosine kinase receptor, is widely known for its essential role in cell survival. Germ line missense mutations, which give rise to constitutively active oncogenic RET, were found to cause multiple endocrine neoplasia type 2, a dominant inherited cancer syndrome that affects neuroendocrine organs. However, the mechanisms by which RET promotes cell survival and prevents cell death remain elusive. We demonstrate that in addition to cytoplasmic localization, RET is localized in the nucleus and functions as a tyrosine-threonine dual specificity kinase. Knockdown of RET by shRNA in medullary thyroid cancer-derived cells stimulated expression of activating transcription factor 4 (ATF4), a master transcription factor for stress-induced apoptosis, through activation of its target proapoptotic genes NOXA and PUMA. RET knockdown also increased sensitivity to cisplatin-induced apoptosis. We observed that RET physically interacted with and phosphorylated ATF4 at tyrosine and threonine residues. Indeed, RET kinase activity was required to inhibit the ATF4-dependent activation of the NOXA gene because the site-specific substitution mutations that block threonine phosphorylation increased ATF4 stability and activated...Continue Reading

References

Apr 1, 1995·Cancer Genetics and Cytogenetics·L D CooleyR F Gagel
Nov 14, 1997·International Journal of Cancer. Journal International Du Cancer·J A VelascoP Santisteban
May 31, 2001·The Journal of Biological Chemistry·R Bagheri-YarmandR Kumar
Dec 20, 2003·The Journal of Biological Chemistry·Tzippi Hershko, Doron Ginsberg
May 4, 2004·Nature Reviews. Cancer·Andreas GschwindAxel Ullrich
Aug 19, 2004·Journal of the National Cancer Institute·Matthias DrostenBrigitte M Pützer
Apr 18, 2006·Proceedings of the National Academy of Sciences of the United States of America·Anupama E GururajRakesh Kumar
Jun 28, 2006·The Journal of Experimental Medicine·Han YouTak W Mak
Feb 7, 2007·The Journal of Biological Chemistry·Sheng-Chieh Hsu, Mien-Chie Hung
Jun 15, 2007·Nature Reviews. Molecular Cell Biology·David Ron, Peter Walter
Nov 29, 2007·Proceedings of the National Academy of Sciences of the United States of America·Mikhail A NikiforovMaria S Soengas
May 7, 2008·The Journal of Experimental Medicine·Philipp S LangeRajiv R Ratan
Jun 27, 2008·Carcinogenesis·Lihua MingJian Yu
Jan 24, 2009·Proceedings of the National Academy of Sciences of the United States of America·Qiuyan WangYihong Ye
Sep 9, 2009·Cellular Signalling·Zamal AhmedJohn E Ladbury
Nov 10, 2009·The Journal of Clinical Endocrinology and Metabolism·Wen ZhuGilbert J Cote
Nov 26, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Samuel A Wells, Massimo Santoro
Dec 22, 2009·The Journal of Biological Chemistry·Jane L ArmstrongChristopher P F Redfern
Feb 18, 2010·Molecular Cell·Jerry E ChipukDouglas R Green
Jul 7, 2010·Cell·Mark A Lemmon, Joseph Schlessinger
Oct 15, 2010·Endocrine-related Cancer·Donata VitaglianoMassimo Santoro
Dec 17, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Zohreh GalehdarSean P Cregan
Feb 14, 2012·Nature Medicine·Kengo TakeuchiYuichi Ishikawa
Feb 14, 2012·Nature Medicine·Takashi KohnoTatsuhiro Shibata
Aug 10, 2012·Molecular Biology of the Cell·Douglas S RichardsonLois M Mulligan
Oct 20, 2012·The Biochemical Journal·Luke R G PikeAdrian L Harris
Nov 17, 2012·Cancer Cell·Guoliang QingM Celeste Simon
Feb 20, 2013·The Journal of Cell Biology·Zamal AhmedJohn E Ladbury
Aug 1, 2014·Nature·Diogo Fonseca-PereiraHenrique Veiga-Fernandes

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Citations

Jul 13, 2016·Endocrine-related Cancer·Antonella VerrientiCosimo Durante
Oct 12, 2016·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Boyu YangXiaoling Liang
Apr 5, 2017·Current Opinion in Clinical Nutrition and Metabolic Care·Christopher M AdamsMichael C Dyle
Jan 13, 2018·Frontiers in Cellular Neuroscience·Priyamvada M PitaleMarina Gorbatyuk
May 12, 2019·International Journal of Molecular Sciences·Marilina García-Aranda, Maximino Redondo
Apr 19, 2017·Oncotarget·Chiaki Tsuge IshidaMarkus David Siegelin
May 26, 2020·Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire·Huan WangZhiwei Su
Jul 25, 2020·Virology Journal·Yuanzhi LiuXiaoyue Chen
Feb 5, 2021·Cancer Immunology Research·Douglas R Green
Mar 23, 2020·Genomics, Proteomics & Bioinformatics·Chenwei WangYu Xue
Sep 9, 2021·Molecular Cancer Therapeutics·Jacob J AdashekVivek Subbiah

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